CD22 is a transmembrane receptor expressed on B cells that functions through recruitment of intracellular inhibitors of activation, in particular SHP-1. CD22 is known to down-regulate signaling mediated through cross-linking of the B cell receptor (BCR). There is some evidence that differences in CD22 activity may be important in SLE. The NZB/W F1 lupus prone mouse possesses an allele of CD22 which responds poorly to LPS induction and a polymorphism of CD22 has been found to associate with lupus in a study of Japanese women. We propose to study the role of CD22 in B cell development and tolerance induction in the mouse. We will analyze levels of CD22 expression that alter thresholds for BCR-mediated apoptosis or activation using tissue culture cell lines and primary B cells. We will determine if CD22 overexpression enhances anti-DNA antibody titers in a mouse transgenic for the heavy chain of an anti-DNA antibody, in a model of lupus in which anti-DNA antibodies are induced by immunization with a peptide mimetope of DNA and in the NZB/W lupus-prone strain. Finally, we will examine whether the lupus-associated polymorphism of CD22 associates with disease in African-American and Hispanic women with SLE and will determine whether high levels of expression of CD22 are present in B cells during periods of disease activity.